DESCRIPTION (Verbatim from the Applicant): The most important risk factor for the development of osteoarthritis (OA) is age but the exact mechanism by which aging contributes to the development of OA is not known. The overall objectives of this proposal are to ascertain the role of IGF-I as a chondrocyte survival factor and establish a model for how an age-related decline in chondrocyte responsiveness to IGF-I contributes to the increased prevalence of OA with age. A decline in the number of chondrocytes in cartilage due to loss of cells from cell death has been noted with aging. Increased cell death has also been noted in OA cartilage. The factors normally responsible for keeping chondrocytes alive are not known. Based on new preliminary studies, the primary working hypothesis for this proposal is that IGF-I functions as a key autocrine survival factor for chondrocytes. A second hypothesis is that signals from the matrix mediated through the integrin family of cell-matrix receptors work in synergy with IGF-I to promote survival in cartilage. In the proposed studies, the link between aging, cell death and IGF-I action will be explored using human ankle cartilage from tissue donors of various ages. Since age-related development of OA in the ankle is uncommon, studies of this tissue can be used to separate effects of aging from effects of degeneration and OA, a problem in studies utilizing cartilage from hips or knees. In selected studies, results will be compared to those obtained using knee chondrocytes to determine if differences exist between cells from the two joints which may relate to the greater propensity for OA to develop in the knee. The Specific Aims are to: 1) Determine if an aging-related reduction in the response to IGF-I results in an increased susceptibility of chondrocytes to cell death; 2) Determine if IGF-I acts in synergy with signals generated from the extracellular matrix via integrins to promote chondrocyte survival and 3) Determine if IGF-I cell survival signaling is impaired in chondrocytes from older adults. The results of these studies will provide important new information needed to better understand the link between aging and osteoarthritis, the most common cause of chronic disability in older adults.